Atomic-Level Characterization of Protein-Protein Association

Abstract

that is critical for the transit of signaling endosomes from dendrites to the nucleus. To further investigate the mechanisms regulating dynein-driven transport, we are testing the hypothesis that motility is precisely regulated by cargo-specific effectors. We focused on Hook1, which induces superprocessive dynein motility in single molecule TIRF assays. We used live cell imaging of hippocampal neurons in microfluidic chambers to investigate the role of Hook proteins in endosomal transport along the axon. Hook1 depletion significantly reduced the flux of BDNF-positive signaling endosomes without affecting the overall motility of Rab5-endosomes. These observations indicate that Hook1 acts as a specific dynein effector for signaling endosomes in the axon, and support the model that differential association with cargo-specific effectors allows for organelle-specific tuning of dynein motor function.

Unbiased Atomistic Insight in the Mechanisms and Solvent Role for Globular Protein Dimer Dissociation

“…Employing reaction coordinate and transition state analysis we found that in the transition states regions only a small fraction (∼ 25%) of the native contacts are present. This conclusion is in agreement with recent straightforward simulation by the DE Shaw group [19]. In addition, we found evidence for an important role of the D33-R40 salt-bridge, also implicated by experiments [29].…”

“…We highlight a configuration containing the three most occurring contacts (R40-D33, H146-S150, I29-S150) in the path ensembles in Figure. 3. These findings signify that the dissociation/association process is not a one step process, and transiently formed interactions occur during the pathway, something that is also observed for the Barnase-Barstar dimer, the Insulin-dimer, and Ras-Raf-RBD, RNase-Hi-SSB-Ct, TYK2-pseudokinase complexes [17,19]. Sakurai et.…”

“…While hydrophobic association/dissociation occurs through the dewetting effect [7,8], association of hydrophilic proteins involves wet dimer native interfaces [9,10], and has received significantly less attention, even though 70% of the protein-protein interfacial residues are hydrophilic [11]. The widely studied hydrophilic dimers Barnase-Barstar or Acetylcholinesterase-Fasciculin associate through a diffusion-limited reaction where the slow step is finding the transient encounter complex, a process accelerated by water assisted electrostatic steering between the charged hydrophilic interfaces [12][13][14][15][16][17][18][19][20][21][22]. However, little is known about hydrophilic dimers whose association is slower and not in the electrostatic steering regime, including many small proteins [23].…”

“…While molecular dynamics (MD) simulation can in principle provide such detailed insight, straightforward MD using all atom force fields is impractical as timescales of dissociation and association are on the order of milliseconds to seconds. Only recently a handful of MD studies addressed hydrophilic dimers (mostly on Barnase-Barstar) [12,17,18,30]. Using Markov State Modeling (MSM) techniques Plattner et.…”

Temperature–Energy-space Sampling Molecular Dynamics: Deterministic, Iteration-free, and Single-replica Method utilizing Continuous Temperature System

“…See reviews [16][17][18] for other methods, various applications, and related topics. Recent developments can be founded in literature [19][20][21][22][23][24].…”